Abstract

Background

The contact factor XII (FXII) activates upon contact with a variety of charged surfaces. Activated FXII (FXIIa) activates factor XI, which activates factor IX, resulting in thrombin generation, platelet activation, and fibrin formation. In both in vitro and in vivo rabbit models, components of medical devices, including extracorporeal oxygenators, are known to incite fibrin formation in a FXII‐dependent manner. Since FXII has no known role in hemostasis and its inhibition is therefore likely a safe antithrombotic approach, we investigated whether FXII inhibition also reduces accumulation of platelets in extracorporeal oxygenators.

Objectives

We aimed to determine the effect of FXII inhibition on platelet deposition in perfused extracorporeal membrane oxygenators in nonhuman primates.

Methods

A potent FXII neutralizing monoclonal antibody, 5C12, was administered intravenously to block contact activation in baboons. Extracorporeal membrane oxygenators were temporarily deployed into chronic arteriovenous access shunts. Radiolabeled platelet deposition in oxygenators was quantified in real time using gamma camera imaging. Biochemical assays were performed to characterize the method of action of 5C12.

Results

The anti‐FXII monoclonal antibody 5C12 recognized both the alpha and beta forms of human and baboon FXII by binding to the protease‐containing domain, and inhibited FXIIa activity. Administration of 5C12 to baboons reduced platelet deposition and fibrin formation in the extracorporeal membrane oxygenators, in both the presence and absence of systemic low‐dose unfractionated heparin. The antiplatelet dose of 5C12 did not cause measurable increases in template bleeding times in baboons.

Conclusions

FXII represents a possible therapeutic and safe target for reducing platelet deposition and fibrin formation during medical interventions including extracorporeal membrane oxygenation.

Details

Title
Antibody inhibition of contact factor XII reduces platelet deposition in a model of extracorporeal membrane oxygenator perfusion in nonhuman primates
Author
Wallisch, Michael 1   VIAFID ORCID Logo  ; Lorentz, Christina U 1   VIAFID ORCID Logo  ; Lakshmanan, Hari H S 2   VIAFID ORCID Logo  ; Johnson, Jennifer 2 ; Carris, Marschelle R 1 ; Puy, Cristina 2 ; Gailani, David 3   VIAFID ORCID Logo  ; Hinds, Monica T 2   VIAFID ORCID Logo  ; McCarty, Owen J T 4   VIAFID ORCID Logo  ; Gruber, András 5   VIAFID ORCID Logo  ; Tucker, Erik I 1 

 Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, USA; Aronora, Inc., Portland, OR, USA 
 Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, USA 
 Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA 
 Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, USA; Division of Hematology & Medical Oncology, Department of Medicine, Oregon Health & Science University, Portland, OR, USA 
 Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, USA; Aronora, Inc., Portland, OR, USA; Division of Hematology & Medical Oncology, Department of Medicine, Oregon Health & Science University, Portland, OR, USA 
Pages
205-216
Section
ORIGINAL ARTICLES: THROMBOSIS
Publication year
2020
Publication date
Feb 2020
Publisher
Elsevier Limited
e-ISSN
24750379
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2362755555
Copyright
© 2020. This work is published under http://creativecommons.org/licenses/by-nc-nd/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.